There must be a way out of here: Identifying a safe and efficient combination of promoter, transgene, and vector backbone for gene therapy of neurological disease

摘要

The long-term therapeutic success of gene therapy for the treatment of neurological diseases will rely in large part on the vector used.1 Clinical success will hinge upon a balance between efficient cell trans-duction to reverse pathological phenotypes, and the extent of adverse inflammatory and immunological neurotoxicity.2 Ciesielska et al. have recently shown that transduc-tion of glial cells in rodents by an adeno-associated virus serotype 9 (AAV9)-based vector expressing green fluorescent protein (GFP) increased immunological neurotoxicity when compared to similar vectors expressing endogenous proteins.3 In this issue of Molecular Therapy, Samaranch et al. dissect further and compare in detail the neuropathology triggered by expression of a non-self or self-protein delivered by AAV9-or AAV2-based vectors in adult nonhuman primates (NHPs). The study highlights the continued challenge of optimizing the combination of promoter, transgene, and vector backbone, and how a simple change in the latter can alter both transduction patterns and toxidty.